The objective of this proposal is to evaluate pharmacologic agents for their potential in the treatment of asthma and the anaphylactic reaction by studying the effects of these agents on a molecular level, and in the whole animal. Several advances in basic knowledge have provided the impetus for this undertaking. First it is now possible to isolate mast cells, which are a primary source of histamine, which mediates the asthmatic and anaphylactic reactions. Second, it has been shown that the relative concentrations of adenosine 3', 5'-cyclic monophosphate (cyclic AMP) and guanosine 3',5'-cyclic monophosphate (cyclic GMP) in the mast cells influence the release of histamine. Third, there are multiple forms of cyclic AMP phosphodiesterase and cyclic GMP phosphodiesterase, the enzymes which hydrolyze the cyclic nucleotides and therefore control their intracellular concentrations. The pattern of these forms of phosphodiesterase appear to be characteristic for each tissue and cell type so far studied. Fourth, the multiple forms of phosphodiesterase can be differentially inhibited by pharmacologic agents. These findings suggest that on the molecular level, an appropriate pharmacologic agent will inhibit one or more of the phosphodiesterase forms which are found in the mast cell, and thus raise the intracellular concentration of cyclic AMP. On the cellular level, this increase in cyclic AMP will inhibit the release of histamine. On the level of the whole animal, inhibition of the release of histamine from mast cells will prevent the onset or decrease the severity of the asthmatic and/or the anaphylactic reaction. The proposal has four specific objectives: 1) The isolation and characterization of the phosphodiesterase forms of mast cells; 2) The identification of pharmacologic agents which most specifically inhibit these phosphodiesterases in vitro; 3) The determination of the effect of these agents on histamine secretion from isolated mast cells in vitro; 4) The determination of the potential clinical significance of these findings by using selected agents in vivo to alter histamine secretion and thereby alter the course of passive cutaneous anaphylaxis in vivo.